Pharmacology of Estrogens and Progestins

1. Introduction/Overview

Estrogens and progestins constitute a fundamental class of steroid hormones with extensive physiological roles and therapeutic applications. These agents are integral to the regulation of the female reproductive system, influencing the menstrual cycle, pregnancy, and secondary sexual characteristics. Beyond their endogenous functions, synthetic and natural derivatives are employed therapeutically to manage conditions ranging from contraception to hormone-sensitive cancers and menopausal symptoms. The clinical relevance of these hormones is profound, impacting a significant proportion of the population across various life stages. A thorough understanding of their pharmacology is essential for safe and effective prescribing, particularly given the nuanced balance between therapeutic benefits and potential risks, including thromboembolic events and carcinogenic potential.

Learning Objectives

• Classify the major types of estrogens and progestins, distinguishing between endogenous forms, conjugated preparations, and synthetic analogs.
• Explain the genomic and non-genomic mechanisms of action mediated through nuclear hormone receptors and membrane-associated receptors.
• Compare and contrast the pharmacokinetic profiles of orally administered versus transdermally delivered estrogens and progestins.
• Evaluate the major therapeutic indications, including hormone replacement therapy, contraception, and management of gynecological disorders.
• Analyze the spectrum of adverse effects, from common side effects to serious risks such as venous thromboembolism and breast cancer, and identify key drug interactions.

2. Classification

Estrogens and progestins are classified based on their chemical structure, origin, and pharmacological activity. This classification informs their therapeutic selection, potency, and side effect profiles.

Estrogen Classification

Estrogens are categorized into three main groups: natural estrogens, conjugated estrogens, and synthetic estrogens.

• Natural Estrogens: These are identical to hormones produced by the human body. The primary forms are 17β-estradiol (E2), estrone (E1), and estriol (E3). Estradiol is the most potent and predominant estrogen in premenopausal women. Estriol is considered a weak estrogen, with high production during pregnancy.
• Conjugated Estrogens: These are mixtures of estrogen salts, primarily derived from pregnant mare’s urine (e.g., Premarin®). They contain sulfate esters of estrone, equilin, and other equine estrogens. Esterified estrogens are a similar mixture from plant or synthetic sources.
• Synthetic Estrogens: These compounds are structurally modified to resist first-pass metabolism, allowing oral administration. Ethinyl estradiol (EE) is the most prominent, featuring an ethinyl group at the C17 position, which markedly increases oral bioavailability and half-life. Mestranol is a prodrug that is metabolized to ethinyl estradiol.
• Selective Estrogen Receptor Modulators (SERMs): While not classic estrogens, this class (e.g., tamoxifen, raloxifene) exhibits tissue-selective agonist or antagonist activity at estrogen receptors and is relevant in comparative pharmacology.

Progestin Classification

Progestins are synthetic compounds that mimic the activity of the natural hormone progesterone. They are classified by their chemical generation, which correlates with their androgenicity, estrogenicity, and other steroid receptor activities.

• First Generation (Estrane Derivatives): Derived from testosterone, these progestins (e.g., norethindrone, norethynodrel) possess some residual androgenic and estrogenic activity. They are used in older oral contraceptives and menopausal therapy.
• Second Generation (Gonane Derivatives): Also derived from testosterone but with reduced androgenicity. Examples include levonorgestrel and norgestrel. They are potent progestins with significant androgenic effects, commonly found in contraceptives.
• Third Generation (Gonane Derivatives): Designed to further minimize androgenic side effects. Examples are desogestrel, gestodene, and norgestimate. Desogestrel is a prodrug metabolized to etonogestrel.
• Fourth Generation and Other Progestins: This group includes newer agents with unique profiles. Drospirenone is an analog of spironolactone with anti-mineralocorticoid and anti-androgenic activity. Dienogest also has anti-androgenic properties. Medroxyprogesterone acetate (MPA) is a derivative of progesterone itself, used in depot injections and menopausal therapy.
• Natural Progesterone: Micronized progesterone formulations are available for oral and vaginal use, offering a bioidentical option with a favorable metabolic and side effect profile but significant sedative effects due to neuroactive metabolites.

3. Mechanism of Action

The pharmacological actions of estrogens and progestins are predominantly mediated through intracellular ligand-activated transcription factors, known as nuclear hormone receptors. Additional non-genomic mechanisms contribute to their rapid physiological effects.

Estrogen Receptor Pharmacology

Estrogens exert their effects primarily by binding to estrogen receptors (ERs), of which two main subtypes exist: ERα and ERβ. These receptors are members of the nuclear receptor superfamily.

• Genomic Signaling Pathway: Upon ligand binding in the cytoplasm, ERs undergo a conformational change, dissociate from chaperone proteins like heat shock protein 90 (HSP90), dimerize, and translocate to the nucleus. The dimer binds to specific DNA sequences known as estrogen response elements (EREs) in the promoter regions of target genes. Receptor binding recruits coactivator or corepressor complexes, which modulate chromatin structure and the recruitment of RNA polymerase II, ultimately regulating gene transcription. The transcriptional profile is highly tissue-specific and depends on the ER subtype (α or β), the ligand, and the cellular context of cofactor expression.
• Non-Genomic (Rapid) Signaling Pathways: Estrogens can also initiate rapid signaling events within seconds to minutes, independent of gene transcription. These effects are mediated by membrane-associated ERs or G protein-coupled estrogen receptor 1 (GPER1). Activation of these receptors triggers second messenger systems, including activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, and increased intracellular calcium. These pathways influence cell proliferation, migration, and vascular tone.
• Receptor Subtype Distribution: ERα is predominantly expressed in the uterus, breast, liver, and hypothalamus, mediating effects on reproductive tissues and hepatic protein synthesis. ERβ is more abundant in the ovary, prostate, bone, vascular endothelium, and central nervous system, often modulating the proliferative effects of ERα.

Progestin Receptor Pharmacology

Progestins act via the progesterone receptor (PR), which exists as two main isoforms, PRA and PRB, generated from a single gene.

• Genomic Signaling: Similar to ERs, ligand-bound PRs dimerize and bind to progesterone response elements (PREs) on DNA, regulating gene expression. The balance between PRA and PRB isoforms can determine cellular response, with PRB generally acting as a stronger transcriptional activator.
• Antagonism of Estrogen Effects: A key therapeutic action of progestins, particularly in endometrial protection, is the down-regulation of estrogen receptors and the induction of 17β-hydroxysteroid dehydrogenase, which converts estradiol to the less potent estrone. Progestins also promote endometrial glandular secretion and stromal decidualization.
• Cross-Reactivity with Other Steroid Receptors: Many synthetic progestins, due to their structural origins, exhibit affinity for other steroid receptors. This cross-reactivity explains their ancillary pharmacological properties:
  • Androgenic Activity: Testosterone-derived progestins (e.g., levonorgestrel) can activate the androgen receptor, potentially causing acne, hirsutism, and adverse lipid changes (decreased HDL-C).
  • Anti-Androgenic Activity: Progestins like drospirenone and dienogest antagonize the androgen receptor, which may be beneficial for treating androgen-dependent conditions.
  • Anti-Mineralocorticoid Activity: Drospirenone antagonizes the aldosterone receptor, leading to potassium retention and a mild diuretic effect.
  • Glucocorticoid Activity: Some progestins, such as medroxyprogesterone acetate, have weak glucocorticoid receptor agonist activity.

4. Pharmacokinetics

The pharmacokinetics of estrogens and progestins vary widely depending on the specific compound, route of administration, and formulation. These factors critically influence dosing regimens, efficacy, and side effect profiles.

Absorption

Absorption is highly route-dependent.

• Oral Administration: Natural estradiol undergoes extensive first-pass metabolism in the gut and liver, converting primarily to estrone sulfate, resulting in low and variable oral bioavailability (approximately 5-10%). Ethinyl estradiol is resistant to this metabolism due to its ethinyl group, yielding high and consistent oral bioavailability (approximately 40-50%). Most synthetic progestins (e.g., norethindrone, levonorgestrel) are well absorbed orally. Micronized progesterone is also absorbed but has low bioavailability due to presystemic metabolism.
• Transdermal Administration: Patches, gels, and sprays deliver estradiol directly into the systemic circulation, bypassing first-pass hepatic metabolism. This results in more physiological estradiol-to-estrone ratios and avoids the hepatic induction of synthesis proteins like renin substrate and clotting factors, which is thought to lower thrombotic risk compared to oral therapy.
• Parenteral Administration: Intramuscular injections of esters (e.g., estradiol valerate, medroxyprogesterone acetate) provide sustained release over weeks to months. Subcutaneous implants offer prolonged delivery for years. Vaginal rings (e.g., releasing etonogestrel/ethinyl estradiol or estradiol) provide local and systemic effects with low daily doses.

Distribution

Estrogens and progestins are highly lipophilic and distribute widely throughout body tissues. In the plasma, they are extensively bound to plasma proteins.

• Estrogens: Circulating estradiol is bound with high affinity to sex hormone-binding globulin (SHBG) and with lower affinity to albumin. Only the unbound fraction (1-3%) is biologically active. Ethinyl estradiol increases hepatic synthesis of SHBG.
• Progestins: Binding varies by compound. Many bind to albumin, while some (like levonorgestrel) also bind to SHBG. The degree of SHBG binding influences free drug concentration and biological activity.

Metabolism

Hepatic metabolism is the primary route of biotransformation, involving cytochrome P450 enzymes (notably CYP3A4), followed by conjugation via glucuronidation and sulfation.

• Estrogen Metabolism: Estradiol is interconverted with estrone via 17β-hydroxysteroid dehydrogenase. Both are then hydroxylated at multiple positions (C2, C4, C16) by CYP enzymes. Catechol estrogens (2- and 4-hydroxyestrogens) can be further metabolized to potentially genotoxic semiquinones/quinones, though they are usually rapidly methylated by catechol-O-methyltransferase (COMT). Metabolites are conjugated and excreted in bile, with some undergoing enterohepatic recirculation.
• Progestin Metabolism: Pathways include reduction of the A-ring and 3-keto group, hydroxylation, and conjugation. Many are metabolized to active compounds; for example, desogestrel is converted to etonogestrel, and norgestimate is converted to norelgestromin and levonorgestrel.

Excretion

Conjugated metabolites are primarily excreted in urine. A portion is excreted in bile, and after deconjugation by gut flora, some parent drug may be reabsorbed (enterohepatic recirculation), particularly for ethinyl estradiol.

Half-life and Dosing Considerations

• Estrogens: The half-life of oral estradiol is short (1-4 hours), necessitating daily or multiple-daily dosing. Ethinyl estradiol has a longer half-life (13-27 hours), supporting once-daily oral contraceptive dosing. Transdermal estradiol patches are typically applied once or twice weekly.
• Progestins: Half-lives vary: norethindrone (~8 hours), levonorgestrel (~15 hours), etonogestrel (~30 hours). Depot medroxyprogesterone acetate (DMPA) is administered every 3 months due to its slow release from the intramuscular site. Levonorgestrel-releasing intrauterine systems provide local effects for 3-8 years with minimal systemic exposure.

5. Therapeutic Uses/Clinical Applications

The clinical applications of estrogens and progestins are diverse, reflecting their broad physiological roles. Therapy often involves balancing estrogenic benefits against risks, with progestins added to mitigate endometrial hyperplasia in women with a uterus.

Hormone Replacement Therapy (HRT) / Menopausal Hormone Therapy (MHT)

The primary indication is the relief of moderate-to-severe vasomotor symptoms (hot flashes, night sweats) and genitourinary syndrome of menopause (vaginal atrophy, dyspareunia).

• Estrogen Therapy (ET): Used in women who have undergone hysterectomy. Can be administered orally (conjugated estrogens, estradiol) or transdermally.
• Estrogen-Progestin Therapy (EPT): Required for women with an intact uterus to prevent estrogen-induced endometrial hyperplasia and carcinoma. Progestin can be administered cyclically (mimicking a menstrual cycle) or continuously.
• Prevention of Osteoporosis: Considered for postmenopausal women at significant risk of fracture when non-estrogen therapies are not suitable. Estrogens inhibit bone resorption by osteoclasts.

Contraception

Combined estrogen-progestin and progestin-only formulations are mainstays of hormonal contraception.

• Combined Oral Contraceptives (COCs): Contain ethinyl estradiol (or estradiol valerate) and a progestin. They suppress ovulation by inhibiting gonadotropin-releasing hormone (GnRH) and thus luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. They also thicken cervical mucus and alter the endometrium.
• Progestin-Only Contraceptives: Include the “mini-pill,” depot injections (DMPA), implants (etonogestrel), and levonorgestrel-releasing intrauterine systems (LNG-IUS). These primarily work by thickening cervical mucus and may also suppress ovulation inconsistently.
• Emergency Contraception: High-dose levonorgestrel or ulipristal acetate (a progesterone receptor modulator) can delay or inhibit ovulation.

Gynecological Disorders

• Dysmenorrhea and Endometriosis: COCs or progestin-only therapies (e.g., DMPA, LNG-IUS, danazol) are used to induce endometrial atrophy and reduce pain.
• Abnormal Uterine Bleeding: High-dose estrogen-progestin combinations can provide acute control. Cyclic or continuous regimens are used for long-term management.
• Hypogonadism and Primary Ovarian Insufficiency: Hormone replacement is used to induce and maintain secondary sexual characteristics and prevent osteoporosis.

Other Therapeutic Uses

• Feminizing Hormone Therapy: Estrogens (often with anti-androgens) are used in transgender women to induce feminine secondary sex characteristics.
• Prostate Cancer: High-dose estrogens (e.g., diethylstilbestrol) were historically used for androgen suppression via negative feedback on the pituitary; their use has declined due to cardiovascular toxicity.
• Acne and Hirsutism: COCs containing anti-androgenic progestins (e.g., drospirenone, norgestimate) can be effective by reducing ovarian androgen production and increasing SHBG.

6. Adverse Effects

The adverse effect profile is extensive, ranging from common, benign side effects to rare, life-threatening complications. Risk is influenced by dose, route, specific compounds, and patient-specific factors such as age and comorbidities.

Common Side Effects

• Estrogen-Related: Nausea, breast tenderness, bloating, fluid retention, and headaches. These often diminish with continued use.
• Progestin-Related: Mood changes, depression, acne, weight gain, and bloating. Androgenic progestins may cause hirsutism or worsen lipid profiles (lowering HDL-C).
• Breakthrough Bleeding: Common during the first few months of combined hormonal contraceptive or HRT use.

Serious Adverse Reactions

• Venous Thromboembolism (VTE): A well-established risk of estrogen-containing products, particularly with oral administration. The risk is highest in the first year of use and is influenced by the progestin type; some data suggest a higher risk with third-generation progestins (desogestrel, gestodene) and drospirenone compared to levonorgestrel. The mechanism involves estrogen-induced increases in hepatic synthesis of clotting factors (II, VII, VIII, X, fibrinogen) and decreased anticoagulant proteins (antithrombin III, protein S). Transdermal estrogen appears to confer a lower risk.
• Arterial Thrombosis (Stroke, Myocardial Infarction): Risk is increased, particularly in older women (>35 years) who smoke or have other cardiovascular risk factors. The risk is very low in healthy, young, non-smoking women.
• Breast Cancer: Long-term use of combined estrogen-progestin HRT is associated with a small but statistically significant increased relative risk of invasive breast cancer, which appears to diminish after discontinuation. Estrogen-only therapy in hysterectomized women shows a less clear or possibly reduced risk. The relationship with combined oral contraceptives is complex, showing a very slight increase in relative risk that disappears 5-10 years after stopping.
• Endometrial Cancer: Unopposed estrogen therapy in women with a uterus significantly increases the risk of endometrial hyperplasia and adenocarcinoma. This risk is eliminated by the concomitant use of adequate progestin.
• Gallbladder Disease: Estrogens increase cholesterol saturation of bile, elevating the risk of gallstone formation.
• Hypertension: Can be induced or exacerbated, particularly with oral estrogens, due to increased angiotensinogen synthesis.
• Hypertriglyceridemia: Estrogens can markedly increase serum triglycerides, posing a risk of pancreatitis in patients with pre-existing severe hypertriglyceridemia.
• Liver Tumors: Rare benign hepatic adenomas and, very rarely, hepatocellular carcinoma have been associated with long-term high-dose estrogen use.

Black Box Warnings

Several estrogen and progestin products carry black box warnings, the strongest FDA-mandated caution. These typically highlight:

• Increased risks of cardiovascular events, breast cancer, and dementia in postmenopausal women using combined estrogen-progestin therapy.
• Increased risks of cardiovascular events and breast cancer in postmenopausal women using estrogen-alone therapy.
• That estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia.
• The risk of serious cardiovascular events from smoking while using combined oral contraceptives, especially in women over 35.

7. Drug Interactions

Significant drug interactions occur primarily through induction or inhibition of metabolic enzymes and alterations in protein binding.

Major Drug-Drug Interactions

• Enzyme Inducers: Drugs that induce hepatic CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) can significantly increase the metabolism of both estrogens and progestins. This can lead to reduced contraceptive or therapeutic efficacy, resulting in breakthrough bleeding or unintended pregnancy. Dose adjustment or use of a non-hormonal backup method is recommended.
• Enzyme Inhibitors: Potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, grapefruit juice) may increase plasma levels of hormones, potentially exacerbating side effects like nausea or thrombosis risk.
• Antibiotics: Broad-spectrum antibiotics (e.g., ampicillin, tetracyclines) are thought to reduce efficacy by disrupting enterohepatic recirculation of ethinyl estradiol through gut bacterial flora alteration, though the clinical significance is debated. It is often considered prudent to recommend backup contraception during and shortly after antibiotic use.
• Other Interactions:
  • Drospirenone: Due to its anti-mineralocorticoid activity, it can increase serum potassium. The risk of hyperkalemia is increased when co-administered with other potassium-sparing drugs (e.g., ACE inhibitors, ARBs, NSAIDs, heparin) or in patients with renal or adrenal insufficiency.
  • Thyroid Hormone: Estrogens increase thyroid-binding globulin (TBG), which may increase the total thyroid hormone requirement in hypothyroid patients.
  • Corticosteroids: Estrogens may potentiate the effects of corticosteroids by inhibiting their metabolism.

Contraindications

Absolute contraindications to estrogen-containing products typically include:

• Known or suspected pregnancy.
• Undiagnosed abnormal genital bleeding.
• Known or suspected estrogen-dependent neoplasia (e.g., breast cancer, endometrial cancer). Exceptions may exist for palliative care.
• Active or history of arterial thromboembolic disease (e.g., MI, stroke) or venous thromboembolism (DVT, PE).
• Active or history of thrombophilic disorders (e.g., protein C, protein S, antithrombin deficiency).
• Severe hepatic dysfunction or liver tumors.
• Hypersensitivity to any component of the formulation.

Relative contraindications require careful risk-benefit assessment and include migraine with aura, hypertension, hypertriglyceridemia, gallbladder disease, and a history of cholestasis during pregnancy.

8. Special Considerations

Patient-specific factors necessitate tailored approaches to prescribing and monitoring therapy with estrogens and progestins.

Use in Pregnancy and Lactation

• Pregnancy (FDA Category X): Estrogens and progestins are generally contraindicated. Diethylstilbestrol (DES) use in pregnancy is a historical example of teratogenicity, causing clear cell adenocarcinoma of the vagina in female offspring. Some progestins may be used in specific circumstances, such as micronized progesterone for luteal phase support in assisted reproduction.
• Lactation: Estrogens can suppress milk production and reduce protein and fat content in breast milk. Progestin-only contraceptives (e.g., the mini-pill, DMPA, implants) are generally considered compatible with breastfeeding and are preferred for postpartum contraception.

Pediatric Considerations

Use is typically restricted to specific indications under specialist care.

• Delayed Puberty: Low-dose estrogen is used to induce puberty in girls with hypogonadism, with doses gradually increased to mimic normal development.
• Contraception in Adolescents: COCs are commonly used and are generally safe. Counseling should emphasize adherence and the increased risk of VTE with smoking.

Geriatric Considerations

In postmenopausal women, the risks of therapy often increase with age.

• Initiating systemic HRT in women aged 60 years or older, or more than 10 years from menopause onset, is generally not recommended due to an unfavorable risk-benefit ratio, particularly concerning coronary heart disease, stroke, VTE, and dementia.
• Low-dose vaginal estrogen therapy for urogenital symptoms remains a safe and effective option in older women, as systemic absorption is minimal.

Renal and Hepatic Impairment

• Renal Impairment: Caution is advised. Estrogens can cause fluid retention. Drospirenone is contraindicated in patients with renal insufficiency or adrenal failure due to the risk of hyperkalemia. Dose adjustments may be necessary for other agents, though specific guidelines are often lacking.
• Hepatic Impairment: Estrogens and progestins are extensively metabolized by the liver. Their use is contraindicated in acute or severe chronic liver disease, including hepatic tumors, due to impaired clearance and the potential to exacerbate liver dysfunction. In mild impairment, use with caution and close monitoring.

9. Summary/Key Points

The pharmacology of estrogens and progestins encompasses a complex interplay of molecular mechanisms, pharmacokinetic variability, and broad clinical utility tempered by significant adverse effect potential.

Summary

• Estrogens and progestins are classified into natural, conjugated, and synthetic categories, with progestins further categorized by “generation,” which predicts ancillary receptor activities (androgenic, anti-androgenic, etc.).
• The primary mechanism of action involves ligand-activated nuclear receptors (ERα/β, PR-A/B) that function as transcription factors, regulating gene expression. Rapid, non-genomic signaling also contributes to their effects.
• Pharmacokinetics are critically dependent on the route of administration. Oral estrogens undergo significant first-pass metabolism, which is circumvented by transdermal or parenteral routes, altering the risk-benefit profile.
• Major therapeutic applications include menopausal hormone therapy, contraception (combined and progestin-only), and management of gynecological disorders like endometriosis and abnormal uterine bleeding.
• Serious adverse effects include an increased risk of venous and arterial thromboembolism, breast cancer (with combined EPT), and endometrial cancer (with unopposed ET). Common side effects are often manageable and transient.
• Significant drug interactions occur with hepatic enzyme inducers (reducing efficacy) and inhibitors (increasing toxicity). Drospirenone has a specific interaction risk with hyperkalemia.
• Special populations require careful management: contraindicated in pregnancy, caution in lactation with estrogens, individualized approaches in adolescents, and generally avoiding initiation of systemic HRT in older postmenopausal women.

Clinical Pearls

• The lowest effective dose for the shortest duration necessary should be used to achieve treatment goals, particularly in menopausal hormone therapy.
• Transdermal estrogen may offer a safer profile than oral estrogen regarding thrombotic risk in patients with risk factors, as it avoids the first-pass hepatic effect on clotting factor synthesis.
• In women with an intact uterus, estrogen therapy must always be combined with a progestin to prevent endometrial hyperplasia and cancer.
• When prescribing combined oral contraceptives, a thorough history should screen for contraindications, with emphasis on smoking status, personal or family history of thrombosis, and migraine with aura.
• Progestin-only contraceptives are preferred for breastfeeding women and may be suitable for women with contraindications to estrogen.
• Patient counseling should clearly articulate both the benefits and risks, enabling informed, shared decision-making.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.